Valproic acid combined with 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic syndromes

Siitonen, Timo; Timonen, T.; Juvonen, Eeva; Terävä, Venla; Kutila, Anu; Honkanen, Tuomo; Mikkola, Maija; Hallman, Heikki; Kauppila, Marjut; Nyländen, P.; Poikonen, Eira; Rauhala, Auvo; Sinisalo, Marjatta; Suominen, Merja; Savolainen, Eeva‐Riitta; Koistinen, Pirjo

doi:10.3324/haematol.11262

Cited by 41 publications

(25 citation statements)

References 20 publications

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“…Median OS was statistically superior in the hydroxyurea arm (20 months versus 9 months). Several other trials evaluated agents such as low-dose cytarabine with or without the use of all-trans retinoic acid [57][58][59], topotecan [60,61], 9-nitro-campothecin (a novel topoisomerase inhibitor) [62], valproic acid (histone deacetylase inhibitor) [63], and lonafarnib (farnesyltransferase inhibitor) [64] in the treatment of CMML. Collectively, response rates in these trials were disappointing and treatment was associated with significant toxicities.…”

Section: Management Of Proliferative Diseasementioning

confidence: 99%

Chronic Myelomonocytic Leukemia: a Genetic and Clinical Update

McCullough

Patnaik

2015

Curr Hematol Malig Rep

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Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder, characterized by peripheral blood monocytosis and overlapping features between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs). Clonal cytogenetic changes are seen in up to 30 % patients, while approximately 90 % have detectable molecular abnormalities. Most patients are diagnosed in the seventh decade of life. Gene mutations in ten-eleven translocation (TET) oncogene family member 2 (TET2) (60 %), SRSF2 (50 %), ASXL1 (40 %), and RAS (20-30 %) are frequent, with only frame shift and nonsense ASXL1 mutations negatively impacting overall survival. With the lack of formal guidelines, management and response criteria are often extrapolated from MDS and MPN. Contemporary molecularly integrated CMML-specific prognostic models include the Groupe Francais des Myelodysplasies (GFM) model and the Molecular Mayo Model, both incorporating ASXL1 mutational status. Hypomethylating agents and allogeneic stem cell transplant remain the two most commonly used treatment strategies, with suboptimal results. Clinical trials exploiting epigenetic and signal pathway abnormalities, frequent in CMML, offer hope and promise.

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Section: Management Of Proliferative Diseasementioning

confidence: 99%

Chronic Myelomonocytic Leukemia: a Genetic and Clinical Update

McCullough

Patnaik

2015

Curr Hematol Malig Rep

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“…Although this study established superiority of hydroxyurea over etoposide, it was regarded to be a nonspecific treatment for such patients. Several other trials evaluated agents such as low-dose cytarabine with or without the use of all-trans retinoic acid [48][49][50], topotecan [51,52], 9-nitro-campothecin (a novel topoisomerase inhibitor) [53], valproic acid (histone deacetylase inhibitor) [54], and lonafarnib (farnesyltransferase inhibitor) [55] in the treatment of CMML. Collectively, response rates in these trials were disappointing and treatment was associated with significant toxicities.…”

Section: Risk-adapted Therapy General Principles Of Treatmentmentioning

confidence: 99%

Chronic myelomonocytic leukemia: 2013 update on diagnosis, risk stratification, and management

Tefferi

2013

American J Hematol

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“…As a result, its marketability to treat acne has overcast some of its more recent applications. For instance, it can be used as a monotherapy or in combination for the treatment of cutaneous T-cell lymphoma (Zhang & Duvic 2003) and oral leukoplakia (Piattellia et al 1999), and as a differentiating agent in myelodysplastic conditions (Siitonen et al 2007). Though 13cRA has multiple applications and therapeutic targets, the cellular mechanisms and molecular targets are not understood.…”

Section: Introductionmentioning

confidence: 99%

13-cis-Retinoic acid specific down-regulation of angiotensin type 1 receptor in rat liver epithelial and aortic smooth muscle cells

Snyder

Thekkumkara²

2011

Journal of Molecular Endocrinology

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Transcriptional repression through cis-and trans-acting factors enabling an alternate approach to control angiotensin type 1 receptor (AT1 or AGTR1 as listed in the MGI database) expression has not been studied. In previous investigations, treatment with retinoic acid was found to be associated with enhanced insulin sensitivity. In our previous study, expression of AT1 was found to be inversely correlated with intracellular glucose concentrations. Therefore, we hypothesized that 13-cis-retinoic acid (13cRA), an antioxidant, enhances insulin-sensitive glucose-mediated downregulation of the AT1. In this study, we used continuously passaged rat liver epithelial cells. Our study shows that cells exposed to 13cRA specifically down-regulated the AT1 protein in a dose-and time-dependent manner, independently of any change in receptor affinity. Down-regulation of the AT1 expression leads to reduced AngII-mediated intracellular calcium release, a hallmark of receptor-mediated intracellular signaling. Similarly with receptor down-regulation, we observed a significant reduction in AT1 mRNA; however, the AT1 down-regulation was independent of insulin-sensitive glucose uptake and retinoic acid receptor activation (RAR/RXR). Treatment with 13cRA resulted in phosphorylation of p42/p44 MAP kinases in these cells. Subsequent studies using MEK inhibitor PD98059 prevented 13cRA-mediated AT1 down-regulation and restored AngII-mediated intracellular calcium response. Furthermore, 13cRA-mediated inhibitory effects on AT1 were validated in primary rat aortic smooth muscle cells. In summary, our results demonstrate for the first time that 13cRA has a glucose-and RAR/RXR-independent mechanism for transcriptional inhibition of AT1, suggesting its therapeutic potential in systems in which AT1 expression is deregulated in insulin-sensitive and -insensitive tissues.

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Valproic acid combined with 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic syndromes

Cited by 41 publications

References 20 publications

Chronic Myelomonocytic Leukemia: a Genetic and Clinical Update

Chronic Myelomonocytic Leukemia: a Genetic and Clinical Update

Chronic myelomonocytic leukemia: 2013 update on diagnosis, risk stratification, and management

13-cis-Retinoic acid specific down-regulation of angiotensin type 1 receptor in rat liver epithelial and aortic smooth muscle cells

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